Tag: 177Lu-J591

From delivering exceptional care in the clinic, to presenting at scientific conferences and publishing research in high-impact medical journals, our Genitourinary (GU) Oncology Program had an exceptionally busy 2018. We continue to work diligently to develop new and more effective therapies to treat advanced prostate, bladder and kidney cancers, while educating the community about cutting-edge advancements in the field.

As we look back on 2018, we wish to share a brief update of our research and accomplishments. Here’s what our team has been up to over the past year.

New FacesMost recently, we were proud to welcome Dr. Cora Sternberg, a global thought-leader in the GU oncology space, to our team. Dr. Sternberg will facilitate the continued growth and development of clinical and translational research programs in GU malignancies, as well as serve as Clinical Director of the Englander Institute for Precision Medicine (EIPM) to develop strategies to incorporate genomic sequencing and precision medicine within our Program and across Weill Cornell Medicine and NewYork-Presbyterian.

New EventsMore than 200 prostate cancer patients and loved ones attended our inaugural New York City Prostate Cancer Summit, a multi-institutional collaboration between Weill Cornell Medicine, NewYork-Presbyterian Hospital, Columbia University Irving Medical Center and Memorial Sloan Kettering Cancer Center. This educational and advocacy event featured presentations and panel discussions from local medical experts and national advocacy leaders, with topics including nutrition, screening, coping and anxiety, immunotherapy and much more. Our second annual Summit is slated for September 2019 during Prostate Cancer Awareness Month. Stay tuned for details.

New Research Developments

Prostate Cancer

• Based upon our prior work with fractionated dosing of our radiolabeled antibody 177Lu-J591, we performed the world’s first phase 1 dose-escalation trial of 177Lu-PSMA-617 without finding any dose-limiting toxicity (no major side effects despite higher and higher doses), presenting the initial results at the European Society for Medical Oncology (ESMO) 2018 Congress. The phase II portion of the trial is ongoing. We are also leading the first trial combining two different targeting agents (J591 and PSMA-617) designed to deliver more radiation to tumors and less to other organs.

• Alpha particles are several thousand-fold more potent than beta-emitters such as 177 Lu. We are completing the phase 1 dose-escalation portion of the world’s first-ever clinical trial utilizing a powerful alpha particle (225Ac) directed almost exclusively at prostate cancer cells by linking it with our J591 antibody, which avoids salivary glands.

• As prostate-specific membrane antigen (PSMA) targeting enters “prime time,” the United States Department of Defense (DOD) has recognized our significant contributions to this evolving field with a grant that will allow us to research optimal patient selection for PSMA-targeted radionuclide therapy and assess the treatment’s immune effects.

• Thanks to developing technology utilizing circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), we are able to draw information about a patient’s tumor via a simple blood test. In our findings published by the American Association for Cancer Research (AACR) Clinical Cancer Research journal, we analyzed the relationship between chemotherapy treatment and expression of androgen receptor (AR) variants in CTCs of men with metastatic prostate cancer.

• We led a phase II clinical trial through the Prostate Cancer Clinical Trials Consortium (PCCTC) and discovered that an aggressive subset of disease called neuroendocrine prostate cancer (NEPC) is driven by a gene with an associated target known as aurora kinase. Further investigation into targeting of the gene may help us to refine therapy for this difficult-to-treat patient population. Our findings were published as a cover story in Clinical Cancer Research.

• Working with collaborators and funded by the Prostate Cancer Foundation (PCF), we have developed unique genomics sequencing methodology called PCF SELECT that allows us to identify actionable mutations in men with advanced prostate cancer.

Kidney Cancer

• The number of United States Food and Drug Administration (FDA)-approved drugs for patients with advanced kidney cancer continues to grow. Dr. Ana Molina leads our team in offering clinical trials focused on novel targeted agents, combination treatments, and risk-directed therapies for various subtypes of kidney cancer.

• Working together with the Englander Institute for Precision Medicine, we are evaluating genetic signatures from patient tumor specimens and developing organoids that can be used to test novel pathways and tailor treatment to each individual patient.

• Laboratory studies of our in vivo kidney cancer models have resulted in discoveries regarding the metabolism of the disease. Understanding the role of the mitochondria (a cell’s power generator) in kidney cancer is leading us to novel therapeutic approaches to block tumors from growing and spreading.

Bladder Cancer

• Five immune therapies are now FDA-approved for people with advanced bladder cancer. We continue research to improve upon these agents by combining them with targeted therapeutics with the potential to replace chemotherapy. Collaboration with EIPM will help us to identify tumors most likely to benefit from these treatments.

• Dr. Bishoy Faltas and his lab team are focused on understanding the role of a specific family of proteins that cause mutations (genetic errors) that may be the underlying cause of bladder cancer. This research will enable us to develop new treatments to target the newly-identified genes that drive the disease.

• Based upon Dr. Faltas’ prior high-impact Nature Genetics publication that identified the genetic mechanisms by which bladder cancers become resistant to chemotherapy and new drug targets, we are launching an innovative new clinical trial utilizing a targeted drug that inhibits bladder cancer growth, the first time this type of drug is being tested in bladder cancer.

• We are conducting clinical trials of two antibody-drug conjugates (sacituzumab govitecan and enfortumab vedotin) designed to deliver potent chemotherapy-like toxins preferentially to cancer cells. This type of therapy is anticipated to become one of the standard approaches to bladder cancer treatment.

Precision Medicine

• Using samples of patient tumors (drawn via needle biopsy), we can create small 3-D tumor representations known as organoids that mimic the way that cancer cells grow within the body and respond to treatment. Our team has worked to develop this exciting new form of precision medicine, which is especially significant for rare cancers with a lack of preclinical models available for study.

We are moving closer to our ultimate goal of curing genitourinary cancers and look forward to continued progress in the years ahead.

We have an open clinical trial using radioimmunotherapy for men who have been diagnosed with prostate cancer, and whose PSAs are rising despite initial hormonal therapy but have no evidence of metastatic disease on scans (no tumors seen on CT/MRI and bone scan). This clinical trial is investigating whether attaching Lutetium 177 with the monoclonal antibody J591 (177Lu-J591) can delay or prevent the disease progression to overt metastatic disease in men with “biochemical progression”.

J591 can recognize a protein antigen known as PSMA (also known as anti-prostate-specific membrane antigen) that is present on the surface of nearly all prostate cancer tumors and circulating tumor cells.

The targeted treatment in this trial uses J591 as a delivery vehicle for the radioactive treatment (Lutetium 177) to be delivered directly to the prostate cancer cells that may be hiding or circulating in the body (for example in lymph nodes, the blood stream or the bones).

The Lutetium 177-J591 treatment approach may be ideal for men who are experiencing rising PSA levels after primary prostate cancer treatment and early hormonal therapy, but whose bone and CT scans remain negative. Even though we can’t detect the presence of cancer on these traditional imaging scans, we know from prior research that these men have what we call “micro-metastatic” disease, meaning that the prostate cancer cells are increasing throughout the body because otherwise PSA levels would not be so high or increasing at such a rapid rate. Unfortunately, even with traditional hormonal manipulation, metastases become evident in these men after months. Although we have treated many men with overt metastatic prostate cancer and demonstrated anti-tumor responses, we have also shown that we are able to target these micro-metastatic sites (tumors that are too small to be seen on CT or bone scan), and the properties of 177-Lu make it more optimal for tumors that are too small to be seen on conventional imaging.

Many patients fall in this category in a broad sense and usually these men feel completely fine. Approximately 50,000 new men per year in the U.S. suffer a biochemical relapse (rising PSA after surgery or radiation) and some of these men will have further PSA rises despite the most common type or hormonal therapy, which are injections to bring down testosterone levels. The goal is to intervene earlier on in order to bring more men to cure and suppress the disease from further progression and metastases.

Men in this phase II study will be randomized and all patients will receive oral hormonal therapy as part of treatment which also serves to boost their PSMA level (i.e. increase the number of “locks” per tumor cell). Since PSMA is the target for 177Lu-J591, radioimmunotherapy increased expression of PSMA can lead to more targeting of the otherwise invisible tumor cells. Two-thirds of patients will receive 177Lu-J591 at the highest tolerated dose that improved outcomes based on our prior study and the remaining one-third will get J591 with a diagnostic isotope (111Indium). The isotope 111-Indium (abbreviated 111In) is also an energetic radioactive particle, but it does not generally give off enough energy to kill cancer cells while still allowing researchers to take more detailed pictures of where the prostate cancer is located in the body.

Our goal is to ultimately cure the men who fall in this category by eradicating microscopic deposits of cancer, and the Weill Cornell Genitourinary Oncology team is available for patient consultations and to speak with physicians who are interested in referring patients to this trial, which is available at a number of sites across the country.

Radiation is a mainstay in the treatment of prostate cancer. In men with localized prostate cancer (confined to the prostate gland), using radiation can help cure the cancer. In men with advanced disease, radiation can improve survival and help to manage pain.

Radiation can be delivered a variety of different ways. For example, there are external beams that can be used to deliver radiation from an external machine into the prostate, radioactive “seeds” that can be implanted, or ways to inject special radioactive isotopes directly into the bloodstream.

In the United States (U.S.), there are older FDA-approved treatments utilizing radioactive isotopes for men with prostate cancer that has spread to the bones to decrease pain, called samarium-153 (brand name Quadramet) and strontium-89 (Metastron). More recently, a bone-targeted alpha particle called radium-223 (brand name Xofigo®) was approved because it leads to longer overall survival in men with symptomatic metastatic castration-resistant bone metastases. These bone-targeted radioisotopes have been useful because prostate cancer commonly spreads to bone. However, those drugs cannot treat other sites of tumors such as in the prostate, lymph nodes, or lung.

We are also able to use parts of the immune system as a way to deliver radioactive particles or other targeted cancer treatments to the prostate cancer. We have engineered very specific monoclonal antibodies and molecules that will bind only to PSMA, leading to the opportunity for “molecularly targeted” radiotherapy for prostate cancer. When we combine immunotherapy with monoclonal antibodies with radioactive isotopes, we call the treatment approach radioimmunotherapy. Radioimmunotherapy involves attaching a radioactive isotope (such as Lutetium 177) to a cancer-targeting antibody or small molecule that binds only to a specific cancer-related molecule on a tumor cell. This is similar to a “lock and key” scenario, where the antibody or molecule serves as a key that will only recognize a very specific lock (the cancer-related molecule). In prostate cancer, nearly all cells have a specific “lock” that lives on the surface of each cell called prostate-specific membrane antigen (PSMA).

For nearly 15 years, we have been utilizing a monoclonal antibody known as J591, which is a version of a specific key that will only recognize and enter cells with the specific lock PSMA. We successfully utilized this antibody tagged with small radioactive particles to either visualize or treat prostate cancer tumors within the prostate, bone, lymph nodes, and other sites in the body. Our initial studies demonstrated safety and signaled anti-tumor efficacy. In addition, we showed that the antibody went to virtually all sites of tumors (sometimes discovering new ones) and did not target other normal organs (with the exception of the liver which helps clear the drug from the body). Subsequently, our larger studies have shown responses in larger numbers of patients. In Europe, physicians picked up on our results and Lutetium 177 (also known as Lu-177, 177-Lu or 177 Lutetium) has become a very popular radioactive particle that can be directed to prostate cancer via PSMA. It has been used to kill prostate cancer cells and treat hundreds of prostate cancer patients. This commonly-used approach uses a small molecule which recognizes PSMA to deliver Lu-177 to prostate cancer cells (termed radioligand therapy or radioimmunotherapy therapy).

Lutetium-177 PSMA therapy is associated with a good prostate cancer response and many men travel from all over the world to Europe in order to access this treatment. In the U.S. it is only available via clinical trials, and for more than 10 years, Weill Cornell Medicine and NewYork-Presbyterian have been one of the few centers in the U.S. to offer Lutetium 177 and other targeted treatments using radioactive particles.